Method for producing lamotrigine from α-oxo-2,3-dichlorophenyl acetamidino-aminoguanidino hydrazone by ring closure reaction

ABSTRACT

The present invention relates to a method for producing 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (lamotrigine) by cyclization reaction from α-oxo-2,3-dichlorophenylacetamidino-aminoguanidino-hydrazone.

The present invention relates to a method for producing Lamotrigine aswell as intermediate products used in the method.

Lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) has theformula I

This compound, disclosed for example in European patent publicationEP-A-0 021 121, is suitable for treating disorders of the centralnervous system, in particular epilepsy, and since 1990 has been used inspasmolytic medications in numerous countries.

To date a variety of methods for producing Lamotrigine have beendisclosed. Common to the methods disclosed in EP-A-0 021 121, EP-A-0 247892, EP-A-0 963 980 and WO 00/35888 is the fact that cyclization of2-(2,3-dichlorophenyl)-2-(guanidinylimino)acetronitrile (formula II)represents the final synthesis step.

The compound of formula II required for the cyclization reaction may beobtained in a variety of ways. The following reaction model illustratesthe reaction sequence disclosed in EP-A-0 963 980:

The methods disclosed in the aforementioned patent applications forproducing lamotrigine by way of a cyclization reaction with a compoundof formula II deviate in individual steps from the reaction sequenceillustrated above. Common to all of them, however, is that the compoundof formula (II) is obtained by reacting 2,3-dichlorobenzoyl cyanide(formula VI) with aminoguanidine. In accordance with the aforementionedpatent applications 2,3-dichlorobenzoyl cyanide is produced by reactionwith copper cyanide from 2,3-dichlorobenzoyl chloride (formula V).

A drawback of the above-described method of synthesis for producinglamotrigine is that the 2,3-dichlorobenzoyl cyanide (formula VI)required for synthesizing the compound of formula II can only beobtained in a form that is oily and difficult to purify, in addition towhich the compound is unstable and prone to dimerization Further, thecopper cyanide needed for synthesis of the 2,3-dichlorobenzoyl cyanide(formula VI) is relatively costly.

Moreover, during synthesis of the 2,3-dichlorobenzoyl cyanide (formulaVI) a contaminant in the form of 2,3-dichlorobenzoe acid anhydride isproduced. According to EP-A-0 963 980 this anhydride can be reacted withlamotrigine in the subsequent reaction sequence to form a compound offormula VII, which is an undesirable impurity.

EP-A-0 963 980 also cites as an additional undesirable impurity acompound of formula VIII

which is produced by hydrolysis of lamotrigine under basic conditions.For this reason, several of the methods of synthesis disclosed in theabove cited patent applications are further disadvantageous because thecyclization reaction of the compound of formula II is performed in ahighly basic environment, such that the undesirable impurity VIII isable to form through hydrolysis even during lamotrigine synthesis.

An alternative method of lamotrigine synthesis is disclosed in WO96/20934, in which the cyclization reaction is performed using acompound analogous to the compound of formula II, which analogouscompound contains an acid amide group instead of the cyanide group. Sucha cyclization reaction must be initiated photochemically, however, andthis is invariably coupled with technical difficulties.

The WO 96/20935 patent publication discloses a method for producinglamotrigine from6-(2,3-dichlorophenyl)-3-methylthio-5-chloro-1,2,4-triazine. Inreplicating this method HPLC was used to identify larger quantities ofunknown by-products in addition to lamotrigine in the reaction mixture.

Hence, there exists a continuing need for methods by which to obtainlamotrigine industrially, as economically as possible and in purestpossible form.

Thus, an object of the present invention was to provide a method forproducing lamotrigine that eliminates the aforementioned drawbacks.

It was found unexpectedly that lamotrigine may be obtained in highlypure form in a cyclization reaction from an intermediate compound notheretofore described.

The present invention thus relates to a method for producing lamotrigineor a pharmaceutically acceptable salt thereof, in which a cyclizationreaction is performed using a compound of formula XII

or a salt thereof, and optionally from which salt of the compound offormula 1 the free base is released and, if desirable, said free base isconverted to a pharmaceutically acceptable salt.

As a result of the cyclization reaction according to the presentinvention with compound XII to lamotrigine, the latter is obtained inhigh yields and in especially pure form under mild conditions. Inaddition, the compound of formula XII is easily accessed using a simplemethod of synthesis and is readily purified by crystallization. Giventhe high purity of the reactant in the cyclization reaction according tothe present invention, as compared to known reactions, it is possible toachieve an especially high purity level of the desired lamotrigine, apurity level required for pharmaceutical preparations, without the needfor complex purification steps. In particular, there were no impuritiesof formulas VII and VIII cited in EP-A-0 963 980 detected in thelamotrigine produced according to the method of the present invention.

The cyclization reaction may be performed by heating under mildconditions, for example, at a temperature in the range of 100°-170° C.,preferably 130°-170° C. It is preferable to perform the cyclizationreaction in solution. Solvents suitable for the compound of formula XIIare all organic solvents that have no adverse affect on the reaction,preferably dimethylsulfoxide or dimethylformamide. Especially preferredare solvents having a boiling point in the desired temperature range,such that the reaction may occur at the boiling temperature of thesolvent under reflux. To adjust a desired boiling temperature it isfeasible to also use solvent mixtures of, for example, dimethylsulfoxideor dimethylformamide and benzol, toluol or xylol.

The cyclization reaction should be performed to the exclusion of wateror substantially to the exclusion of water.

The cyclization reaction may be performed with the free base of thecompound of formula XII or with an acid addition salt of said compound.A preferred acid addition salt is dihydrochloride. When the cyclizationreaction is performed using an acid addition salt, the product obtainedis the acid addition salt of lamotrigine. In such case, the freelamotrigine base may, if desired, be obtained in nearly quantitativeyield in a manner known to one skilled in the art, e.g. using aqueoussodium hydroxide solution in dimethylformamide.

The time required for the cyclization reaction is a function of theprocess conditions and in particular the temperature at which thereaction is performed. The time can range, for example, from 1-24 hours.An optimal time period is easily determined by one skilled in the art.

In a preferred embodiment of the method according to the presentinvention, the compound of formula XII required for the cyclizationreaction is obtained by reacting a compound of formula XI

in which R is a substituted or unsubstituted straight- orbranched-chained, or cyclical alkyl-, aryl- or aralkyl-residue, or asalt thereof, with aminoguanidine or a salt thereof.

In the compound of formula XI, R may be a straight-chained, branched orcyclical alkyl residue, preferably C₁₋₂₀—, in particular C₁₋₁₀-alkylresidue, such as for example methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, tert-butyl or cyclohexyl. Preferred alkyl residuesfor R are phenyl and naphthyl, in particular phenyl. Preferred aralkylresidues for R are aryl-C₁₋₅-alkyl residues, wherein aryl is defined asabove, and in particular benzyl.

The aforementioned alkyl-, aryl-, and aralkyl-residues may optionallybear one or more, in particular 1 or 2 substitutents such as for examplehalogen, hydroxy, C₁₋₈-alkoxy or nitro. The aryl- and aralkyl-residuesmay be substituted in addition to, or alternatively, with C₁₋₆-alkyl.

R is preferably phenyl.

The compound of formula XII is produced by reacting the compound offormula XI with aminoguanidine or a salt thereof, preferably withaminoguanidine-hydrochloride. The reaction takes place preferably in thepresence of a potent mineral acid, e.g. hydrochloric acid. A suitablesolvent is in principal any solvent that does not adversely affect thereaction. It is preferable to perform the reaction in water or in analcohol. The reaction temperature is not otherwise restricted and mayrange, for example, from between 40°-120° C.

When the compound of formula XI is reacted in the presence ofhydrochloric acid, the dihydrochloride of the compound of formula XII isobtained. This may then either be directly converted by cyclizationreaction to lamotrigine-hydrochloride, as described above, or, ifdesired, the free base of the compound of formula XII may be obtainedprior thereto in a manner known to one skilled in the art, e.g. usingaqueous sodium hydroxide solution.

In a particularly preferred embodiment of the method according to thepresent invention the compound of formula XI or a salt thereof isobtained by reacting a compound of formula X

in which R is as defined above, first with an alcohol solution of ahydrohalic acid, then with NH₃. This reaction path is especiallyadvantageous because the compound of formula X is surprisingly stableand is readily purified by crystallization. The prior art, analogcompound of formula X, 2,3-dichlorobenzoyl cyanide, used in thesynthesis of lamotrigine is an oily, unstable product difficult topurify and it contributes significantly to the contamination of thelamotrigine obtained through synthesis, whereas the compound of formulaX is crystalline and stable, making it is easy to purify. For thisreason the method according to the present invention makes it possibleto produce even at this point in the synthesis path an especially purelamotrigine, since already the intermediate stages themselves may beobtained in especially pure form. Moreover, it is possible to obtain thecompound of formula X, as is further explained below, by reaction withsodium cyanide in lieu of copper cyanide used in the prior art forsynthesizing 2,3-dichlorobenzoyl cyanide. Sodium cyanide is lessexpensive than copper cyanide, hence it is possible to synthesizelamotrigine using the method of the present invention in an overallhighly economical and cost effective manner.

Conversion of the compound of formula X to the compound of formula XIproceeds in two steps, in which said compound is first reacted with analcohol solution of a hydrohalic acid, preferably a methanol or ethanolhydrochloric acid solution, then with NH₃, e.g. by addition of ethanolsaturated with ammoniac. Both reaction steps may be performed, forexample, in a temperature range of between −30° and +10° C.

When the reaction of the compound of formula X is performed in thepresence of hydrochloric acid, hydrochloride of the compound of formulaXI is obtained. This product may, if needed, be used again in the methodaccording to the present invention after purification, e.g. throughre-crystallization, and without releasing the free base.

The α-iminonitriles of formula X are easily accessed, e.g. as describedin German laid-open publication No. 2 221 771. However, in a preferredembodiment of the method according to the present invention, thecompound of formula X is produced by reacting a nitrone of formula IX,

in which R is as defined above, with a cyanide. The advantage of thisvariation over and against the prior art method of producing lamotrigineis that cyanide in the form of sodium cyanide may be used, whichcompared to copper cyanide used in the prior art methods is lessexpensive and easier to handle.

The nitrone of formula IX may be reacted with cyanide, preferably sodiumcyanide, for example in an aqueous buffer, for example a phosphate,acetate or tartrat buffer, in particular a phosphate buffer, at e.g. apH-value in the range of 4-8. It is advantageous to use as a co-solventa low alcohol, preferably methanol. The reaction may occur within abroad temperature range, e.g. from ambient temperature to about 80° C.

The nitrone of formula IX is obtained, for example, according to themethod described by M. P. Grammaticakis in Bull. Soc. Chim. Fr. [1951],p. 971.

Further, the present invention relates to compounds of formulas IX, X XIand XII and salts thereof which occur as intermediate products in themethod according to the present invention. Still further, the presentinvention relates to the use of compounds of formulas IX, X, XI and XIIor salts thereof for producing lamotrigine.

Lamotrigine produced by the method according to the present invention issuitable for the manufacture of pharmaceutical compositions, in which inparticular pharmaceutically acceptable salts of lamotrigine are used.Suitable pharmaceutically acceptable salts and suitable pharmaceuticalcompositions are described, for example, in EP-A-0 021 121, EP-A-0 247892 and WO 96/20935.

The method according to the present invention is described below ingreater detail with reference to but not limited to the followingexamples.

EXAMPLE 1

α-(phenylimino)-2,3-dichlorophenyl acetonitrile (X)

635 mMol of N-(2,3-dichlorophenylmethylene)anilin-N-oxide (IX) aredissolved in a 5.61 mixture (1:1) of an aqueous 0.5 molar solution ofpotassium dihydrogenphosphate and methanol adjusted to pH5. To this areadded 65 g (1.3 Mol) of sodium cyanide in 200 ml water at approximately50° C. During the reaction the pH balance is held constant between 8.0and 8.5. After the reaction is complete (DC control), the reactionmixture is neutralized and cooled to 0° C. The separated yellow-browncrystals are then dissolved in methylene dichloride. The organic phaseis washed in water, dried and evaporated under vacuum. The residue isrecrystallized from a small amount of methanol.

Yield: 157 g Purity: 99.0% (HPLC) Melting point: 65°-67° C.

The NMR spectroscopic data correspond to the chemical structure.

EXAMPLE 2

α-(phenylimino)-2,3-dichlorophenyl acetamidine-hydrochloride (XI-HCL)

151.2 g of α-(phenylimino)-2,3-dichlorophenyl acetonitrile (X) areintroduced in an ethanol hydrochloric acid solution (made from 400 mlethanol, 240 ml thionylchloride and 52 ml water) at −10° C. and stirredat that temperature for several hours. The reaction mixture is thencombined at −10° C. with 6.51 ethanol saturated with ammoniac andstirred for 12 hours at room temperature. The reaction solution is thenconcentrated by evaporation and the product thereof precipitated outwith the addition of water, filtered and dried. The product (XI-HCL) maybe further purified through re-crystallization from acetone.

Yield: 166.7 g Purity: 99.7% (HPLC) Melting point: 263°-267° C.

The NMR spectroscopic data correspond to the chemical structure.

EXAMPLE 3

α-oxo-2,3-dichlorophenylacetamidino-aminoguanidino-dihydrochloride(XII-2HCL) 82.5 g (250 Mmol) ofα-phenyllimino-2,3-dichlorophenylacetamidine-hydrochloride (XI-HCL) areintroduced after gas formation has subsided in a solution of 83.2 g (550mMol) aminoguanidine-bicarbonate (purity: 90%) in 500 ml of 10 mhydrochloric acid and heated to reflux. An equal amount ofα-phenyllimino-2,3-dichlorophenylacetamidine-hydrochloride (XI-HCL) isadded again, and the reaction mixture is maintained at this temperaturefor several hours until the reaction is completed.

Upon completion the reaction is cooled to 0° C. and the precipitatedproduct is filtered off and washed in ice water. The hygroscopic productmay be substantially dried by maintaining it for a lengthier period oftime in vacuum at a slightly elevated temperature.

Yield: 160.0 g (91.5%) g Purity: 99.0% (HPLC) Melting point: 218°-220°C. (decomposed)

EXAMPLE 4

α-oxo-2,3-dichlorophenylacetamidino-aminoguanidino-hydrazone (XII)

The free base of the dihydrochloride (XII-2HCL) may be obtained byconventional means using aqueous sodium hydroxide solution.

Melting point: 2000-203° C.

EXAMPLE 5

Lamotrigine-hydrochloride (L-HCL)

20.76 g ofα-oxo-2,3-dichlorophenylacetamidino-aminoguanidino-hydrazone-dihydrochloride(XII-2HCL) (water content below 0.05%) are heated to reflux in drydimethylformamide for approximately 20 hours. The residue obtained afterextraction of the solvent is briefly heated to boiling with 200 mlisopropanol, then cooled to 20° C. The precipitated crystals arefiltered off and re-crystallized from an aqueous isopropanol (volumeratio 1:1) and dried in vacuum at 80° C.

Yield: 10.6 g (60.5%) Purity: 99.5% (HPLC) Melting point: 233°-235° C.(decomposed)

The free lamotrigine base may be obtained in nearly quantitative yieldby conventional means by being released with aqueous sodium hydroxidesolution in dimethylformamide.

Melting point: 216°-217° C.

EXAMPLE 6

Lamotrigine (1)

8.19 g of α-oxo-2,3-dichlorophenylacetamidino-aminoguanidino-hydrazone(XII) (max. water content 0.3%) are dissolved in 150 ml of drydimethylformamide at 60° C. The solution is evaporated by around 20%under vacuum, after which the temperature is raised to reflux andmaintained at this temperature for 1.5 hours. The reaction mixture isthen concentrated by evaporation and cooled to room temperature, afterwhich 6.7 g of the crude product are isolated, which for purificationare re-crystallized from isopropanol.

Yield: 5.1 g (66.7%) Purity: 99.9% (HPLC) Melting point: 215.5°-216.5°C. (decomposed)

What is claimed is:
 1. Method for producing a compound of formula I

or a pharmaceutically acceptable salt thereof, in which a cyclizationreaction is performed with a compound of formula XII

or a salt thereof and, optionally, from which salt of the compound offormula I thus obtained the free base is released and, if desired, saidfree base is converted to a pharmaceutically acceptable salt.
 2. Methodaccording to claim 1, in which the cyclization reaction is performed byheating.
 3. Method according to claim 2, in which the cyclizationreaction is performed at a temperature in the range of between 100° C.and 170° C.
 4. Method according to claim 1, in which the cyclizationreaction is performed using an acid addition salt, of the compound offormular XII.
 5. Method according to claim 4, wherein the acid additionsalt is the dihydrochloride of the compound of formular XII.